Bone is a dynamic tissue, and homeostasis in the adult skeleton requires a balance between bone resorption and bone formation. Osteoclasts and osteoblasts play a key role in this balance, with osteoclasts initiating bone resorption and osteoblasts synthesizing and depositing new bone matrix. Imbalances in bone homeostasis are associated with such conditions as osteoporosis, Paget""s disease, and hyperparathyroidism.
The activities of osteoclasts and osteoblasts are regulated by complex interactions between systemic hormones and the local production of growth factors and cytokines. Calcitonin, a peptide hormone secreted by the thyroid and thymus of mammals, plays an important role in maintaining bone homeostasis. Calcitonin inhibits bone resorption through binding and activation of a specific calcitonin receptor on osteoclasts (The Calcitoninsxe2x80x94Physiology and Pharmacology, Azria (ed.), Karger, Basel, Su., 1989), with a resultant decrease in the amount of calcium released by bone into the serum. This inhibition of bone resorption has been exploited, for instance, by using calcitonin as a treatment for osteoporosis, a disease characterized by a decrease in the skeletal mass often resulting in debilitating and painful fractures. Calcitonin is also used in the treatment of Paget""s disease where it provides rapid relief from bone pain, which is frequently the primary symptom associated with this disease. This analgesic effect has also been demonstrated in patients with osteoporosis or metastatic bone disease and has been reported to relieve pain associated with diabetic neuropathy, cancer, migraine and post-hysterectomy. Reduction in bone pain occurs before the reduction of bone resorption.
Salmon calcitonin has been shown to be considerably more effective in arresting bone resorption than human forms of calcitonin. Several hypotheses have been offered to explain this observation: 1) salmon calcitonin is more resistant to degradation; 2) salmon calcitonin has a lower metabolic clearance rate (MCR); and 3) salmon calcitonin may have a slightly different conformation, resulting in a higher affinity for bone receptor sites.
Despite the advantages associated with the use of salmon calcitonin in humans, there are also disadvantages. For treatment of osteoporosis, for instance, the average cost can exceed $75 a week and involve daily prophylactic administration for 5 or more years. In the United States, calcitonin must be administered by injection, and since the disease indications for this drug are not usually life threatening, patient compliance can be low.
Furthermore, resistance to calcitonin therapy may occur with long-term use. What triggers this resistance or xe2x80x9cescape phenomenonxe2x80x9d is unknown (see page 1093, Principles of Bone Biology, Bilezikian et al., (eds.) Academic Press, NY; Raisz et al., Am. J. Med. 43:684-90 (1967); McLeod and Raisz, Endocrine Res. Comm. 8:49-59 (1981); Wener et al., Endocrinology 90:752-9 (1972); and Tashjian et al., Recent Prog. Horm. Res. 34:285-303 (1978)). Use of calcitonin mimetics, either in place of native calcitonins or in rotation with native calcitonins, would help avoid resistance to such treatment during long-term use. In addition, some patients develop antibodies to non-human calcitonin, calcitonin mimetics would be useful for such patients.
What is needed in the art are alternative methods of inhibiting bone resorption. Surprisingly, the present invention fulfills these and other needs.
The present invention provides isolated compounds that are calcitonin mimetics. As used herein, the term xe2x80x9ccalcitonin mimeticxe2x80x9d refers to a compound with the ability to mimic the effects generated by calcitonin""s interaction with its receptor and, by such interaction, stimulate G-protein-mediated activation by adenylate cyclase. As a result, these compounds are useful in the treatment of diseases which are mediated by calcitonin. Included among the calcitonin mimetics of the present invention are piperazine derivatives in which each of the nitrogens in the piperazine ring are alkylated or acylated with substituted aryl groups.
In view of the present discoveries, the invention provides methods for the inhibition of bone resorption which is useful for the treatment of osteoporosis, Paget""s disease, hyperparathyroidism, osteomalacia, periodontal defects (bone loss prevention), hypercalcemia of malignancy, idiopathic hypercalcemia of infancy and other conditions. The calcitonin mimetics can also be used to inhibit gastric secretion in the treatment of acute pancreatitis and gastrointestinal disorders, and as analgesics, in particular for bone pain. The calcitonin mimetics described herein may be used alone or in combination with other therapeutic agents.
In other aspects, the present invention provides libraries of calcitonin mimetics which are attached to a solid support, or attached to multiple solid supports. The present invention further provides methods of preparing the libraries as well as methods of screening the libraries to determine relative binding efficiencies of the attached piperazine derivatives to the calcitonin receptor.